The emergence and worldwide prevalence of New Delhi metallo-beta-lactamase 1 (NDM-1) expressing Gram-negative bacteria with resistance against most beta-lactam antibiotics pose a serious threat to human health. However, no NDM-1 inhibitors are clinically approved at present. Herein, based on the lead compound captopril, a series of compounds were designed, synthesized, and evaluated for NDM-1 inhibitory activities. All designed compounds showed single digit micromolar or submicromolar NDM-1 inhibitory activities, which were much more potent than that of captopril. Among them, compounds 14a and 14m exhibited excellent NDM-1 inhibitory activities, with IC50 values of 0.10 and 0.12 mu M, respectively. Further studies demonstrated that compound 14m displayed low cytotoxicity, good water solubility, high metabolic stability, and low acute toxicity in mice. Importantly, compound 14m exhibited potent synergistic antimicrobial activities with Meropenem (MEM) for the treatment of clinically isolated NDM-1-expressing strains.
[1]Fudan Univ, Dept Nat Prod Chem, Sch Pharm, 826 Zhangheng Rd, Shanghai 201203, Peoples R China;
[2]Fudan Univ, Huashan Hosp, Inst Chinese Integrat Med, 12 Wulumuqi Zhong Rd, Shanghai 200040, Peoples R China;
[3]Fudan Univ, Huashan Hosp, Inst Antibiot, 12 Wulumuqi Zhong Rd, Shanghai 200040, Peoples R China;
[4]Minist Hlth, Key Lab Clin Pharmacol Antibiot, 12 Wulumuqi Zhong Rd, Shanghai 200040, Peoples R China;
[5]Fudan Univ, State Key Lab Mol Engn, 220 Handan Rd, Shanghai 200433, Peoples R China;
[6]Fudan Univ, Inst Biomed Sci, 220 Handan Rd, Shanghai 200433, Peoples R China
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